MIXING/BLENDING & GRANULATION SUBMITTED BYSUBMITTED TO ABDUL MUHEEMDR. YASMEEN M.PHARM II SULTANA SEMESTER DOP DOP PHARMACEUTIC
DEFINITION• Mixing may be defined as a unit operation that aims to treat two or more components, initially in an unmixed or partially mixed state, so that each unit (particle, molecule etc.) of the components lies as nearly as possible in contact with a unit of each of the other components.• Mixing aims at reducing non- uniformity in one or more of the properties of a material in bulk.
Main aim of the mixing process is the production of a blend whose sample reflects exactly, or at least by pre-defined accuracy, the ratio of the added base materialsMixing operation may involve: single phase system (e.g., blending of miscible solutions or fast chemical parallel reactions.)multiphase systems (e.g., solid powders, dispersion/suspension, emulsification)
Types of mixtures• Types of mixturesMixtures may be categorized into three types.• Positive mixtures - Positive mixtures are formed from materials such as gases or miscible liquids which mix spontaneously and irreversibly by diffusion, and tend to approach a perfect mix.• Negative mixtures- With negative mixtures the components will tend to separate out. If this occurs quickly, then energy must be continuously input to keep the components adequately dispersed, e.g. with a suspension formulation, such as calamine lotion.
• Neutral mixtures - Neutral mixtures are said to be static in behaviour, i.e. the components have no tendency to mix spontaneously or segregate spontaneously once work has been input to mix them. Examples of this type of mixture include mixed powders, pastes and ointments
• Depending upon the relationship between the shear rate and the applied shear stress, the fluids may be divided into:Newtonian FluidsNon-Newtonian fluids
Newtonian flow:• For it the rate of shear is proportional to the applied stress.• Such fluid have a dynamic viscosity independent of flow rate.
Non Newtonian fluid:• Rate of shear is not proportional to applied stress.• These exhibit dynamic viscosity that are a function of shear stress.
1.Bulk transport:•The movement of relatively large portion of thematerial being mixed from one location in thesystem to another.•This is usually accomplished by means of paddles,revolving blades, or other devices within the mixerarranged so as to move adjacent volumes of fluidin different direction.
2.Turbulent mixing:• It is the direct result of turbulent fluid flow which is characterized by a random fluctuation of the fluid velocity at any given point within the system.• The fluid velocity at a given instant may be expressed as the vector sum of its component in the X,Y,and Z direction.• Turbulent flow, the fluid has a different instantaneous velocities at different location at same instant in time.
3.Laminar mixing:• Streamline or laminar flow is frequently encountered when highly viscous fluid are being processed.• When two dissimilar liquids are mixed through laminar flow the shear that is generated stretches the interface between them.• If the mixer employed forces the layer back upon themselves ,the number of layer, and hence the interfacial area increase exponentially with time.
4.Molecular diffusion:• Primary mechanism responsible for mixing at the molecular level is diffusion resulting from the thermal motion of molecules.• When it occurs in conjugation with laminar flow, molecular diffusion tends to reduce the sharp discontinuities at the interface between the fluid layers• Process if allowed for sufficient time results in complete mixing
EQUIPMENTS.Equipment Selection, Factors: Physical properties of the materials to be mixed…like density, viscosity, and miscibility. Economic considerations regarding processing, e.g. Time required and power expenditure necessary, and Cost of equipment and its maintenance
Equipments:ImpellersDistinction between impellers is made on the basis of : A. Type of flow pattern they produce• Radial flow• Axial flow• Tangential flowB. Shape and pitch of blades
Propellers :Propellers primary induce axial flow and a very little tangential flow.Intense turbulence occurs in the immediate vicinity of the propellers.They are most effective when they are run at high speed in liquids of relatively low viscosity.
Turbines:Blades do not have constant pitch throughout their length.When radial and tangential flow is desired blades set at 90-degree angle to their shaft are employedTilted blades produce axial flow similar to propellers.Suitable for viscous fluid( viscosity 1000 times greater than fluid in which propellers operates.
Paddles:Normally operates at low speeds ( 50 rpm).Blade have a large surface area in relation to tanks in which they are employed.Circulation is primarily tangential.Effectively mix viscous liquid and semisolids.
2. Air jets:Subsurface jets of air or less commonly of some other gas, are effective mixing devices for certain liquids.Liquid must be of low viscosity, non foaming ,unreactive with gas, and nonvolatile.Jets are so arranged that the buoyancy of bubbles lift liquids from the bottom to the top of the mixing vessel
Fluid jets:When liquids are to be pumped into a tank for mixing, the power required for pumping often can be used to accomplish the mixing operation.Fluid are pumped through nozzles arranged to permit good circulation of material throughout the tank.They create somewhat turbulent flow in the direction of their axis.
• Most of the multiparticulate solids as bulk powders or tablet granules behave somewhat like fluids.• Well mixed powders are often observed to undergo substantial segregation during routine handling.Variables effecting solid mixing:- Particle size and particle size distribution are important since they largely determine the magnitude of forces, gravitational and inertial. The particles having mean particle size less than 100microns are considered to be free flowing. The variables like density, elasticity , surface roughness, and shape also exert their influence on the bulk properties of powders.
Mixing mechanismSolid mixing proceeds by the combination of one or more mechanism.1.Convective mixing2. Shear mixing3. Diffusive mixing
1.Convective mixing:Mechanism is analogous to bulk transport in fluid mixing.Convective mixing can occur bya. An inversion of the powder bedb. Blades or paddlesc. Revolving screwd. Any method of moving relatively large mass of material from one part of the powder bed to another.
2. Shear mixing:Depending on flow characteristic these can occur singly or in such a way to give rise to laminar flow.When shear occurs between regions of different composition and parallel to their interface ,it reduce the scale of segregation by thinning the dissimilar layers.It thus reduces the scale of segregation.
3.Diffusive mixing:• Mixing by diffusion is said to occur when random motion of particles within a powder bed causes them to change position relative to one another.• Such an exchange of positions by the single particle results in reduction of intensity of the segregation.• It occurs at the interfaces of dissimilar regions that are undergoing shear and therefore results from shear mixing.• It may also be produced by any form of agitation that results in interparticulate motion.
PROBLEMS RELATED TO MIXING. SegregationParticles tend to segregate due to differences in the size, density, shape, and other properties of the particles of which they are composed.Powders that are not free-flowing or that exhibit high forces of cohesion or adhesion b/w particles are difficult to mix due to agglomeration.Clumps can be broken by use of mixers that generate high shear forces.However these are less susceptible to segregation due to high interparticulate forces that resist interparticulate motion leading to unmixing
• Problem of segregation is worse when one is working with free flowing, cohesion less, or nearly cohesion less particulate matter.• Segregation has been also attributed by mixers.• Those that generate principally convective motion have been classified as non-segregating.• While those producing shear or diffusive mixing are classified as segregating.
• Two quantities to describe the degree of mixing –namely the scale of segregation & the intensity of segregation.• Scale of segregation –analogous to the scale of turbulence, expressed in two ways-• The linear scale may be considered to represent an average value of the diameter of the lumps present.• Volume scale roughly corresponds to the average lumps to the average lump volume• Intensity of segregation is a measure of the variation in composition among the various portions of the mixture. When mixing is complete –intensity of segregation is zero.
Equipment for solid mixing Most common are mixers which consists of containers of one or several geometric forms, which are mounted and can be rotated. Resulting tumbling motion is accentuated by means of baffles or simply by virtue of shape of the container. TWIN-SHELL BLENDER/TUMBLING MIXERS Quite effective because the bulk transport and shear are accentuated by this design.
•Efficiency is dependent on speed of rotation.•Optimum rotation is 30-100 rpm.
STATIONARY CONTAINER TYPE:-It employs a stationary container to hold the material and bring about mixing by means of moving screws, paddles, or blades.Useful in mixing solids that have been wetted and therefore are in a sticky or plastic state.Well known mixers include1. The Ribbon blender:• Consists of horizontal cylindrical tank usually opening at the top and fitted with helical blades.
• The blades are mounted on shaft through the long axis of the tank and have both right and left hand twist
HELICAL FLIGHT MIXERS• Powders are lifted by a centrally located vertical screw and allowed to cascade to the bottom of the tank.
Granulation• Granules are aggregations of fine particles of powders in a mass of about spherical shape
Why we prepare granules when we have powders?1. To avoid powder segregation, if the powder is composed of particles with different dimensions & different densities, a separation between these particles will occur.2. To enhance the flow of powder, Higher flow ability gives better filling of the dies or containers, during a volumetric dosage.
3. Granules have higher porosity than powders,4. To improve the compressibility of powders.5. The granulation of toxic materials will reduce the hazard of generation of toxic dust, which may arise during the handling of the powders.6. Materials, which are slightly hygroscope, may adhere & form a cake if stored as a powder.
• Technologically, granules are used according to two visions:1. As a true & proper pharmaceutical dosage form ,These granules are used to prepare an instant solution or suspension.Granules, can be packaged as: Bulk granules (Multi-dosage containers), Divided granules (Mono-dosage containers ).
2.Semi-finished products for the preparationof tablets or other dosage forms.Usually, granules have an excellentcompressibility,
Granulation technology on large scale by various techniques
GRANULE GROWTH AND CONSOLIDATION.
Mechanisms of Granulation There are Five Particle Bonding Mechanisms, Adhesion and cohesion forces in the immobile liquid films Interfacial forces in mobile liquid films within the granules Formation of solid bridges after solvent evaporation Attractive forces between solid particles Mechanical interlocking
Mechanisms of Granulation Adhesion and cohesion forces in immobile liquid films between individual primary powder particles. Interfacial forces in mobile liquid films Solid bridgesPartial mellting, Binder hardening, crystalization of dissolved sub. Attractive forces between solid particles Mechanism of granule formation
Steps to make powder ready for compression Weighing Mixing Granulation Screening Drying Screening Lubrication Compression 46
Dry granulators: Sluggers Roller Compactors Is used when…… Effective dose of drug is too high for direct compression Drug is sensitive to heat or moisture or both. 48
Wet granulators Shear mixer granulator 49 High speed granulator Fluidized bed granulator Spray driers
WET GRANULATION: some equipment….High Shear Littleford Lodige Mixer/GranulatorGranulator Littleford MGT Granulator Diosna Granulator Gral Mixer/GranulatorGranulator with Fluidized Bed GranulatorDrying Facility Day Nauta Mixer Processor Double cone/Twin Shell Processor Topo GranulatorSpecial Granulator Roto Granulator Marumerizer 50
Wet granulation equipment shear granulator
SOP Of Shear Mixture Granulator: Mixed powder are fed in to the bowl Granulating liquid is added The moist mass has then transferred to a granulator such as oscillating granulator
Disadvantage Long duration Large number of equipment are needed High material loss Advantage Not very sensitive to the material End point can be determined by inspection
High speed granulator Widely used in pharmaceutical SS mixing bowl containing a three blade main impeller, revolves in horizontal plane, and a three blade auxiliary chopper –revolves vertical or horizontal plane Unmixed powder –in the bowl mixed for few minute with rotating impeller Granulation
High speed granulator
Diosna Mixer / Granulator Rapid Mixer Granulator (RMG) Gives more normal PSD with lesser fines. Typical Time Sequence Mixing – 2 minutes Granulation – 8 minutes Discharge – 1 minutes blade chopper 56
Rapid Mixing Granulator: (RMG) 57
Advantage Mixing,Massing,Granulation in a single equipment within few minutes Disadvantage End point monitor needed
Suction FanDesigns of FB granulators Top spray Fabric Filter Bag Bottom spray Spray Nozzle Air Filter Rotating disc granulator Air Heater Product Bed Granulating solution
Fluidized Bed Granulator
Fluidized Bed GranulatorAdvantage One unit so saving labour cost, transfer loses and time 2-6 time greater heat transfer than tray dryer Uniform drying….prevent mottling. Process can be automated once parameters optimizedDisadvantage Expensive Multiple process variable Filter clocking, demixing, electrostatic charge, solvent explosion
Fluidized Bed Granulator (Industrial Equipment) 62
Merumizer (spheronizer) Wet mass containing drug, diluents and binder is pass through extruder to get rod shaped segments. Screw-feed Extruder Cylinder Segments are placed in MERUMIZER where they are shaped into sphere by centrifugal and frictional forces produced by rotating plates/blades and form granules Advantage Granules with regular size, shape with lower friability, so less amount of fines.
Other More Specialized Granulators Spray Driers
References:1. Lachman leon, Liberman A. herbeart “The Theory and Practice of Industrial pharmacy” 3rd edition, page 3-202. Gilber S banker and C.T.Rhodes, Modern pharmaceutics 2nd edition.3. Cooper and Guns “tutorial pharmacy” 6th edition ‘Mixing’.4. C.V.S Subramanium’’Pharmaceutcal engineeering” 3rd edition ‘Mixing’.